Nonalcoholic fatty liver disease (NAFLD) is an increasingly important public health problem world-wide. It is conservatively estimated that -25% of the general US population has NAFLD. -25% of such individuals may develop steatohepatitis (NASH) and as many as 3% of these ultimately may require liver transplant. Development of NAFLD and its progression to chronic disease appears to be multifactorial and is poorly understood in the vast majority of individuals. Based on evidence to date, genetic predisposition coupled with environmental factors, such as diet, are involved. Our long term goal is to identify genes involved in the development and progression of NAFLD. We discovered that mixed genetic background (129;B6) mice spontaneously developed the entire spectrum of NAFLD when fed a Western diet. In preliminary studies of the two parental strains, 129 mice developed NASH by 15 weeks, but B6 mice developed a mild steatosis only. These results allow us to propose the following two independent specific aims: Specific Aim 1: To determine chromosomal regions that confer susceptibility to Western diet-induced NAFLD by quantitative trait locus (QTL) analyses of F2 generation mice derived from parental mouse strains 129S1/SvlmJ (129) and C57BI/6J (B6). a. To phenotype for NAFLD-related traits and to genotype F2 generation mice fed the Western diet. b. To use bioinformatic analyses to determine NAFLD-associated QTLs, including linked and epistatic. Specific Aim 2: To assess innate differences in 129 and B6 parental mouse strains and their F1 progeny. a. To determine genome-wide gene expression differences between parental strains using replicated oligonucleotide microarray analysis. b. To determine dominance of NAFLD phenotypic traits using a F1 generation breeding strategy. The major goal of the proposed work is to discover chromosomal regions and genes that confer susceptibility to the entire spectrum of NAFLD. Knowledge of the genetic factors that influence development of NAFLD and its progression would lead to development of rational prevention and treatment strategies, including design of specific gene-targeted pharmacological interventions, development of prognostic or diagnostic indicators and would enable identification of at risk populations and individualization of therapies.